Compounds broadly identified as 8-NHR quinolines are well known as valuable anti-parasitic agents in clinical medicine and are specifically used in the treatment of conditions resulting from the presence in the blood and tissues of parasites. See, Reduced 8-Aminoquinoline Analogs As Potential Anti-malarial Agents, Carrol et al., J. of Md. Chem. 19, 1111 (1976).
Considerable difficulty however, has been experienced in the past in synthesizing specific compounds or in purifying a compound to produce these quinolines in pharmaceutically acceptable forms. For example, one synthesis procedure uses two equivalents of an 8-NH.sub.2 quinoline in a reaction with a substituted alkyl halide (hereinafter RX). In this reaction one equivalent is consumed in taking up the acid (HX) liberated in the reaction. In this instance then the 8-NHR quinoline products must be purified, and the starting material 8-NH.sub.2 quinoline must be recovered. Both purification of the product, and recovery of the starting material involve costly skilled labor and are time consuming.
Other means for synthesis of the 8-NHR quinolines give lower yields than the foregoing process, or less product, or both, and are often accompanied by a product that is difficult to purify. The process of this invention, however, for the synthesis of 8-NHR quinolines has been found to be broadly applicable to a wide variety of such compounds, and provides a good quality product in satisfactory yields.
The process of this invention to produce 8 amino quinoline derivatives involves the discovery that if a basically substituted halide (RX) is reacted with 8-NH.sub.2 quinoline in the presence of an acid acceptor such as an amine, the requisite side chain will be added to form 8-NHR quinoline and the acid acceptor will form an amine salt which may be readily separated from the pure product.
The present invention, then, consists in the interaction of 8-aminoquinoline compounds with RX, a substituted alkyl halide, in the presence of an amine as an acid acceptor. Suitable amines having boiling points in the range of 80.degree.-90.degree. include triethylamine and diisopropylamine, and from the standpoint of broadest applicability, triethylamine is preferred. The acid acceptor, then, facilitates the reaction and simplifies purification of the product. The process of this invention, then, provides 8-NHR quinoline chemotherapeutic agents at decreased cost of production. Moreover, the instant method renders accessible a variety of 8-NHR quinolines of diverse structural types in good yield. In most cases the compounds formed are of a purity adequate for ready formation of pharmaceutically acceptable salts.
The reaction may be carried out in the presence of an alcohol solvent such as ethanol or 2-ethoxyethanol as a reaction medium. It has been discovered that such alcohols facilitate the interaction of the 8-NH.sub.2 quinoline with the RX in the presence of the amine acid acceptor. In certain instances, reagents are heated together without solvent at temperatures in the range of 100.degree.-175.degree. C. Upon completion of the reaction the HX salt of the acid acceptor is removed as will be hereinafter described.
The 8-NHR quinoline compound formed by the reaction of this invention may be the desired drug itself, or an intermediate from which a desired drug may be formed. Therefore the general freedom from contaminants in the product is of practical importance whether the product is the end result or an intermediate. In the former instance, direct formation of a pharmaceutically acceptable salt from the product is facilitated, and in the latter, clean conversion to requisite products does not demand tedious purification of intermediates.
Accordingly, it is an object of this invention to provide a new process for producing chemotherapeutic agents in high yields and of high purity.
It is another object to provide a process for forming alkyl substituted quinoline compounds useful as chemotherapeutic agents or as intermediates for the formation of chemotherapeutic agents from a 8-aminoquinolines.
It is still another object to provide an efficient process for producing 8-amino substituted quinolines by reacting 8-aminoquinolines with the desired substituent alkyl halide in the presence of an amine which acts as an acid acceptor to provide a product which may be readily separated from the amine acid salt formed as a byproduct.
It is still another object of this invention to provide a process for producing a wide variety of structurally related 8-NHR quinolines which process is both efficient and adaptable to a wide variety of starting materials consisting of reacting 8-aminoquinoline with an alkyl halide in the presence of an amine having a boiling point in the range of 80.degree.-90.degree. C. to form said product and an amine salt.
These and other objects will become readily apparent with reference to the following description and examples.
The following are specific examples of the process of this invention synthesizing diverse 8-NHR quinolines, which examples illustrate the broad applicability of the process of this invention. The following examples illustrate both formation of the 8-NHR quinolines, a pharmaceutically acceptable salt thereof, or use of the product formed as an intermediate to form a more valuable derivative. As such, the examples are intended to be illustrative and not limiting the scope of the instant invention.
As described above, the instant invention is based upon the interaction of 8-NH.sub.2 quinoline type compounds with a substituted alkyl halide (RX) in the presence of a suitable amine such as triethylamine or diisopropylamine. The HX salt of the amine formed by the reaction is then separated and the 8-NHR quinoline obtained for direct use, or conversion to a pharmaceutically acceptable salt for therapeutic application, or for transformation into another 8-NHR quinoline of greater chemotherapeutic worth. In the following examples all temperatures are specified as degrees Celsius.